WO2018183122A1 - Composés inhibiteurs de kinase 1 (ask 1) de régulation du signal de l'apoptose - Google Patents

Composés inhibiteurs de kinase 1 (ask 1) de régulation du signal de l'apoptose Download PDF

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Publication number
WO2018183122A1
WO2018183122A1 PCT/US2018/024130 US2018024130W WO2018183122A1 WO 2018183122 A1 WO2018183122 A1 WO 2018183122A1 US 2018024130 W US2018024130 W US 2018024130W WO 2018183122 A1 WO2018183122 A1 WO 2018183122A1
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pyridin
compound
triazol
isopropyl
benzamide
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PCT/US2018/024130
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English (en)
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Martin W. Rowbottom
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Sidecar Therapeutics, Inc.
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Priority to JP2019553030A priority Critical patent/JP2020512976A/ja
Priority to US16/497,695 priority patent/US11345676B2/en
Priority to EP18776981.5A priority patent/EP3601250A4/fr
Publication of WO2018183122A1 publication Critical patent/WO2018183122A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • Described herein are compounds that are apoptosis signal-regulating kinase 1 (ASKl) inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASKl activity.
  • ASKl apoptosis signal-regulating kinase 1
  • ASKl a serine threonine kinase, activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx.
  • JNK c-Jun N-terminal kinase
  • p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx.
  • JNK c-Jun N-terminal kinase
  • p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx.
  • ASKl has been found to be involved in the development of fibrosis, cancer, diabetes, cardiovascular
  • ASKl inhibitors and uses thereof.
  • the ASKl inhibitors described herein have the structure of Formula (I), or a pharmaceutically acceptable salt thereof.
  • described herein is a compound of Formula (I), or a pharmaceuticall acceptable salt thereof:
  • n 0, 1, 2, or 3;
  • Ci-C 6 alkyl substituted or unsubstituted Ci-C 6 fluoroalkyl, substituted or unsubstituted Ci-C 6 deuteroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, or substituted or unsubstituted -Ci-C 4 alkylene-N(R 5 ) 2 ;
  • L 1 is linker that is -X 2 -, L 2 , -L 2 -X 2 -, -X 2 - L 3 -, or -L 2 -X 2 - L 3 -;
  • R 6 is H, Ci-C 6 alkyl, Ci-Cefluoroalkyl, or Ci-C 6 deuteroalkyl;
  • L 2 is substituted or unsubstituted Ci-C 4 alkylene, substituted or unsubstituted C 2 -
  • L 3 is Ci-C 4 alkylene
  • X 1 is CR 2 or N
  • X 2 is CR 2 or N
  • R 3 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-
  • Cefluoroalkyl or substituted or unsubstituted Ci-C 6 deuteroalkyl
  • ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl
  • ring C is a 5-membered heteroaryl
  • each R 4 is independently selected from Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -Ci 0 cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl and substituted or unsubstituted heteroaryl;
  • each R 5 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, Ci-
  • the compound is an aminoalkyl compound. In some embodiments, the compound is an aminomethyl compound. In some embodiments, the compound is an aminoalkyl compound that has the structure of Formula (IV), or a pharmaceutically acceptable salt, or solvate thereof. In some embodiments, the compound is an aminomethyl compound that has the structure of Formula (IV), or a pharmaceutically acceptable salt, or solvate thereof.
  • n 0, 1, 2, or 3;
  • L 4 is Ci-C 4 alkylene, Ci-C 4 fluoroalkylene, or Ci-C 4 deuteroalkylene;
  • L 1 is linker that is -X 2 -, L 2 , -L 2 -X 2 -, -X 2 - L 3 -, or -L 2 -X 2 - L 3 -;
  • R 6 is H, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, or Ci-C 6 deuteroalkyl;
  • L 2 is substituted or unsubstituted Ci-C 4 alkylene, substituted or unsubstituted C 2 -
  • L 3 is Ci-C 4 alkylene
  • X 1 is CR 2 or N
  • X 2 is CR 2 or N
  • R 3 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-
  • Cefluoroalkyl or substituted or unsubstituted Ci-C 6 deuteroalkyl
  • ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl
  • ring C is a 5-membered heteroaryl
  • each R 4 is independently selected from Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl and substituted or unsubstituted heteroaryl;
  • each R 5 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, Ci-
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
  • described herein is a method of treating a disease or condition in a mammal that would benefit from the inhibition of apoptosis signal-regulating kinase 1 (ASKl) activity comprising administering to the mammal a compound, or pharmaceutically acceptable salt, or solvate thereof, as described herein.
  • ASKl apoptosis signal-regulating kinase 1
  • a method of treating a disease or condition in a mammal that would benefit from the inhibition of apoptosis signal-regulating kinase (ASKl) activity and lysyl oxidase like-2 (LOXL2) activity comprising administering to the mammal a compound, or pharmaceutically acceptable salt, or solvate thereof, as described herein.
  • ASKl apoptosis signal-regulating kinase
  • LXL2 lysyl oxidase like-2
  • the inhibition of ASK1 inactivates c-Jun N-terminal protein kinase, p38 MAP kinase, or a combination thereof.
  • the disease or condition is fibrosis, cancer, an autoimmune disease or condition, an inflammatory disease or condition, a cardiovascular disease or condition, a neurodegenerative disease or condition, or combinations thereof.
  • the disease or condition is fibrosis.
  • the fibrosis comprises lung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis or cutaneous fibrosis
  • described herein is a method of treating or preventing any one of the diseases or conditions described herein comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof.
  • described herein is a method for the treatment or prevention of fibrosis in a mammal comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
  • the fibrosis is amenable to treatment with an ASK1 inhibitor.
  • the fibrosis is liver fibrosis.
  • the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) adminstered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is administered on a continuous daily dosing schedule.
  • any of the aforementioned aspects involving the treatment of a disease or condition are further embodiments comprising administering at least one additional agent in addition to the administration of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • each agent is administered in any order, including simultaneously.
  • the mammal is a human.
  • compounds provided herein are administered to a human.
  • compounds provided herein are orally administered.
  • Articles of manufacture which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of ASK1, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition or reduction of the ASK1 activity, are provided.
  • MAPKs Mitogen-activated protein kinases
  • MAPK networks are critical for the transmission of extracellular signals into appropriate intracellular responses, such as, but not limited to cell growth, differentiation, inflammation, and apoptosis.
  • Prototypical MAPK activation employs a three-kinase core module consisting of a MAPK kinase kinase (MAPKKK or MAP3K) that phosphorylates and activates a MAPK kinase (MAP2K, MEK, or MKK) that in turn phosphorylates and dramatically increases the activity of one or more MAPKs.
  • MAPKKK MAPK kinase kinase
  • MAP2K MAPK kinase kinase
  • MEK MEK
  • MKK MAPK kinase kinase
  • Apoptosis signal-regulating kinase 1 is a member of the MAP3K family that activates the c-Jun N-terminal protein kinase (JNK) and p38 MAPK.
  • ASK1 also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), is activated by a variety of stimuli including hyperglycaemia, transforming growth factor beta (TGF- ⁇ ), oxidative stress, reactive oxygen species (ROS), lipopolysaccharides (LPS), tumor necrosis factor alpha (T Fa), Fas ligand (FasL), endoplasmic reticulum (ER) stress, and increased intracellular calcium concentrations.
  • TGF- ⁇ transforming growth factor beta
  • ROS reactive oxygen species
  • LPS lipopolysaccharides
  • T Fa tumor necrosis factor alpha
  • FasL Fas ligand
  • ER endoplasmic reticulum
  • ROS have been reported to be associated with increase of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS. ASKl induces apoptosis, fibrosis and metabolic dysfunction by activating the p38 and JNK1 pathways.
  • ASKl undergoes activation via autophosphorylation at Thr838 in response to these signals and in turn phosphorylates MAP2Ks, such as MKK3/6 and MKK4/7, which then phosphorylate and activates p38 and JNK MAPKs, respectively.
  • ASK2 is a related MAP3K that shares 45% sequence homology with ASKl .
  • ASK2 tissue distribution is restricted, in some cell types ASKl and ASK2 have been reported to interact and function together in a protein complex. In non-stressed conditions, ASKl is kept in an inactive state through binding to its repressor thioredoxin (Trx) and through association with AKT.
  • Trx repressor thioredoxin
  • ASKl protein can lead to apoptosis or other cellular responses depending on the cell type.
  • ASKl activation and signaling have been reported to play a role in a broad range of diseases including fibrosis, neurodegenerative, cardiovascular, inflammatory, autoimmunity, and metabolic disorders.
  • ASKl has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain, liver and kidney.
  • Fibrosis is a wound-healing process in which there is excessive deposition of extracellular matrix (ECM).
  • ECM is composed of collagens, noncollagen glycoproteins, matrix bound growth factors, glycosaminoglycans, proteoglycans and matricellular proteins, which provide the scaffolding of both the normal and the fibrotic tissues.
  • glycoproteins e.g. cellular fibronectin, laminin, SPARC, osteonectin, tenascin and von Willebrand factor
  • glycosaminoglycans e.g.
  • perlecan perlecan, decorin, aggrecan, lumican and fibromodulin
  • Non-alcoholic steatotic hepatitis is an exemplary type of fibrosis implicating ASK1 activity.
  • NASH-associated fibrosis Multiple pathways are involved in NASH-associated fibrosis including inflammasome-TLR activation and generation of the inflammatory cytokines, increased levels of hedgehog signalling, changes in lipid and glucose metabolism leading to oxidative stress, hepatocyte injury via apoptosis, cell death inducing inflammatory and pro-fibrogenic pathways in nonparenchymal cells and infiltrating immune cells.
  • HSC activation which is the source of excessive deposition of extracellular matrix (ECM) in the parenchyma.
  • ECM extracellular matrix
  • disclosed herein are methods of treating fibrosis with a compound disclosed herein.
  • Fibrosis refers to the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. Fibrosis may refer to the development of fibrous connective tissue as a reparative response to injury or damage. Fibrosis may also refer to the connective tissue deposition that occurs as part of normal healing or to the excess tissue deposition that occurs as a pathological process.
  • a method of reducing fibrosis in a tissue comprising contacting a fibrotic cell or tissue with a compound disclosed herein, in an amount sufficient to decrease or inhibit the fibrosis.
  • the fibrosis includes a fibrotic condition.
  • the fibrosis comprises liver fibrosis, kidney fibrosis, lung fibrosis, cardiac fibrosis, peritoneal fibrosis, ocular fibrosis or cutaneous fibrosis.
  • the fibrosis comprises liver fibrosis.
  • the fibrosis comprises kidney fibrosis.
  • the fibrosis comprises cardiac fibrosis.
  • the fibrosis comprises lung fibrosis.
  • the fibrosis comprises peritoneal fibrosis.
  • the fibrosis comprises ocular fibrosis.
  • the fibrosis comprises cutaneous fibrosis.
  • reducing fibrosis, or treatment of a fibrotic condition includes reducing or inhibiting one or more of: formation or deposition of extracellular matrix proteins; the number of pro-fibrotic cell types (e.g., fibroblast or immune cell numbers); cellular collagen or hydroxyproline content within a fibrotic lesion; expression or activity of a fibrogenic protein; or reducing fibrosis associated with an inflammatory response.
  • the fibrotic condition is liver fibrosis.
  • Liver fibrosis refers to the scar tissue and nodules that replace liver tissue and disrupt liver function.
  • the scar tissue blocks the portal flow of blood through the organ therefore disturbing normal function. Damage to the hepatic parenchyma due to inflammation leads to activation of the stellate cell, which increases fibrosis through production of myofibroblasts and obstructs blood flow in the circulation.
  • Non-alcoholic fatty liver disease is a common liver disease characterized by fat accumulation in hepatocytes that is not linked to excessive alcohol intake and is correlated with obesity, insulin resistance, and cardiac diseases.
  • NAFLD is categorised into simple steatosis and non-alcoholic steatotic hepatitis (NASH), the latter of which can lead to hepatic fibrosis, hepatic cirrhosis, and liver cancer.
  • High fat diet (HFD) is used to induce hepatic steatosis in mouse models. HFD causes fat accumulation and fatty acid oxidation, which leads to ROS generation and subsequent hepatocyte dysfunction and cell death in the liver.
  • TNFa-deficient mice show reduced hepatic steatosis, indicating that proinflammatory cytokines including TNFa are required for liver injury.
  • TNFa-induced apoptosis of hepatocytes is mediated by ASK1-JNK activation.
  • ASKl -deficient mice have reduced HFD-induced hepatic steatosis, fibrosis, and TGFp expression, which is responsible for hepatic fibrosis.
  • Olmesartan, an ATI blocker also improves HFD-induced hepatic steatosis by inhibiting ASKl .
  • olmesartan or ASKl deficiency can attenuate HFD-induced cardiac inflammation and fibrosis, and vascular endothelial dysfunction and remodelling.
  • the ASKl pathway has been shown to be activated in human NASH liver biopsies.
  • animals with established NASH Fl/2
  • a small molecule inhibitor of ASKl significantly reduced hepatic steatosis and fibrosis and significantly improved key metabolic parameters associated with NASH.
  • Treatment with a small molecule inhibitor of ASKl resulted in a significant reduction in body weight; decreased fasting blood glucose and insulin levels; reduction in plasma AST, ALT and cholesterol levels; a reduction in hepatic steatosis; a reduction in liver
  • hydroxyproline a reduction in alpha smooth muscle actin and p-P38 expression; a reduction in fibrillar collagen area and reduced synthesis of collagen.
  • ASKl inhibition also reduced hepatic fibrosis, steatosis and insulin resistance and normalised fatty acid synthesis and lipid metabolism.
  • the fibrotic condition is a fibrotic condition of the lung.
  • Lung or pulmonary fibrosis refers to a number of conditions that cause interstitial lung damage, followed by accumulation of extracellular matrix constituents and eventually loss of lung elasticity and function. These conditions lead to symptoms such as persistent coughing, chest pain, difficulty breathing and fatigue. Lung fibrosis may occur as a secondary condition in various diseases.
  • the fibrotic condition is a fibrotic condition of the heart.
  • Cardiac fibrosis refers to the damage of the heart areas due to myocardial infarction or Davies' disease. Cardiac fibrosis can affect the valves in the heart as well as the muscles, which become stiff and less compliant. This can increase the risk of heart failure.
  • the fibrotic condition is a fibrotic condition of the kidney.
  • Kidney fibrosis refers to an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease.
  • the pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation.
  • Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial -mesenchymal transition, have been identified as the major ways for the generation of the matrix-producing cells in diseased conditions.
  • transforming growth factor-beta TGF- beta
  • TGF- beta transforming growth factor-beta
  • the fibrotic condition is a fibrotic condition of the skin.
  • the fibrotic condition is a fibrotic condition of the eye.
  • the fibrotic condition is a fibrotic condition of the
  • the fibrotic condition is a fibrotic condition of the bone marrow.
  • the fibrotic condition is idiopathic.
  • the fibrotic condition is associated with (e.g., is secondary to) a disease (e.g., an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and/or a connective disease); a toxin; an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarette smoking, a wound); a medical treatment (e.g., surgical incision, chemotherapy or radiation), or a combination thereof.
  • a disease e.g., an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and/or a connective disease
  • a toxin e.g., an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarette smoking, a wound); a medical treatment (e.g., surgical incision, chemotherapy or
  • a method for the treatment or prevention of fibrosis in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • disclosed herein is a method of improving lung function in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • the mammal has been diagnosed as having lung fibrosis.
  • a method of treating idopathic pulmonary fibrosis in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • disclosed herein is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in a tissue of a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the tissue results in fibrosis.
  • a method for the treatment or prevention of scleroderma in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • a method for reducing undesired or abnormal dermal thickening in a mammal comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the dermal thickening is associated with scleroderma.
  • described herein is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in tissues of a mammal comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the dermal tissues results in fibrosis.
  • described herein is a method of reducing hydroxyproline content in tissues of a mammal with fibrosis comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a
  • compounds described herein are used in the treatment of fibrosis associated with arthrofibrosis, Crohn's Disease, Dupuytren's contracture, keloids, myelofibrosis, Peyronie's disease, or scleroderma/systemic sclerosis.
  • anti-fibrotic strategies include (i) removing the injurious stimuli, (ii) suppressing or modulating inflammation, (iii) protecting the organ at risk of developing fibrosis, and (v) promoting matrix degradation. Some of these strategies have direct effect on fibrosis pathway, while others may have indirect effect.
  • anti-fibrotic strategies in NASH include (a) removing the injurious stimuli, (b) suppressing or modulating hepatic inflammation, (c) protecting the liver, (d) downregulating stellate cell activation and (e) promoting matrix degradation.
  • Fibrosis such as hepatic fibrosis in NASH, is driven by multiple risk factors that may interact with each other via several inter-related mechanistic pathways. It is plausible that the injurious stimuli may be heterogenous, but the resultant response in laying down of collagen and worsening of fibrosis may be a common response. In some embodiments, multiple targets may be required to reverse or halt fibrosis. Removal of cause would be the most efficient way to improve fibrosis. This has been supported by observations seen with other chronic diseases, including hepatitis C and B.
  • compounds described herein are dual inhibitors and inhibit the activity of ASK1 and at least one other fibrosis promoting protein. In some embodiments, compounds described herein inhibit the activity of ASK1 and LOXL2.
  • Lysyl oxidase like-2 (LOXL2) is a member of the lysyl oxidase (LOX) family, which comprises Cu 2+ and lysine tyrosylquinone (LTQ)-dependent amine oxidases.
  • the family comprises five genes: lox (LOX), /ox/7 (lysyl oxidase like-1, LOXL1), loxl2 (LOXL2), loxl3 (lysyl oxidase like-3, LOXL3), and loxl4 (lysyl oxidase like-4, LOXL4).
  • the LOX family is known for catalyzing the oxidative deamination of the ⁇ -amino group of lysines and
  • LOXL2 has been demonstrated to have intracellular functions aside from its role in remodeling of the extracellular matrix.
  • LOXL2 positively regulates the epithelial-to- mesenchymal transition (EMT) transducer, Snail 1, by promoting Snail 1 stability and functional activity.
  • EMT epithelial-to- mesenchymal transition
  • Snail 1 epithelial-to- mesenchymal transition
  • FAK focal adhesion kinase
  • LOXL2 The modulation of cell adhesion and cell polarity has been reported to be mediated by intracellular LOXL2.
  • LOXL2 has been more recently described to be associated with chromatin and reported to be involved in histone H3 deamination, a function that is dependent on the LOXL2 catalytic domain.
  • LOXL2 has been shown to be involved in fibrotic processes. Fibrotic processes include an excessive deposition of extracellular matrix components, such as collagen, which alters the physical, biochemical and biomechanical matrix properties leading to defective organ function and organ failure. Tissue fibrosis is also associated with cancer progression by direct promotion of cellular transformation and metastasis. Tumors are typically stiffer than normal tissue and tumor rigidity influences tumor metastasis.
  • Elevated LOXL2 is also associated with fibrotic lesions from livers of patients suffering from diseases or conditions such as, but not limited to, Wilson disease, primary biliary cirrhosis, PSC, NAFLD and NASH. Additionally, the administration of a LOXL2-specific monoclonal antibody AB0023 was efficacious in reducing disease in a model of fibrosis. AB0023 was shown to inhibit the production of growth factors and of crosslinked collagenous matrix and TGF-beta signaling.
  • Cardiovascular diseases include, but are not limited to, ischaemia/reperfusion injury, cardiac remodelling, and vascular endothelial dysfunction.
  • compounds described herein are used in the treatement of diseases of the retina.
  • compounds described herein are used in the treatement of diseases of the spinal cord.
  • ASKl plays a role in the pathogenesis of ventricular remodelling by promoting apoptosis or cardiomyocyte hypertrophy.
  • ASKl is aldosterone- induced cardiac inflammation and fibrosis through induction of monocyte chemoattractant protein (MCP)-l and transforming growth factor (TGF)-pi expression, respectively.
  • MCP monocyte chemoattractant protein
  • TGF transforming growth factor
  • Neurodegenerative disorders include, but are not limited to, Huntington's disease (HD), spinobulbar muscular atrophy, spinocerebeller ataxia (SCA), Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Normal -tension glaucoma.
  • HD Huntington's disease
  • SCA spinobulbar muscular atrophy
  • SCA spinocerebeller ataxia
  • ALS Amyotrophic lateral sclerosis
  • Alzheimer's disease Parkinson's disease
  • Normal -tension glaucoma Normal -tension glaucoma.
  • Inflammatory diseases include, but are not limited to, multiple sclerosis, rheumatoid arthritis.
  • compounds described herein are used in the treatement of respiratory diseases.
  • ASKl also plays a role in airway remodelling, an irreversible hypertrophic change that occurs in chronic bronchitis.
  • Leukotriene D4 has been suggested to activate ASKl and induce AP-1 activation in airway smooth muscle cells, leading to airway remodelling.
  • Respiratory diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), asthmas and acute lung injury.
  • COPD chronic obstructive pulmonary disease
  • asthmas and acute lung injury.
  • TNFa is one of the factors that aggravate insulin resistance.
  • TNFa induces ROS production in the mitochondria and activates JNK via ASKl, which leads to insulin receptor substrate-1 (IRS-1) serine phosphorylation.
  • IRS-1 insulin receptor substrate-1 serine phosphorylation.
  • Such phosphorylation decreases tyrosine phosphorylation of IRS-1 resulting in insulin resistance and eventually causing type 2 diabetes.
  • compounds described herein are used in the treatement of liver linjury.
  • Consumption of large quantities of acetaminophen a widely used analgesic and antipyretic agent, is known to cause liver injury.
  • acetaminophen a widely used analgesic and antipyretic agent
  • INK acetaminophen-induced, sustained activation of INK is suppressed and resistance to liver injury increased, indicating that the ASKl -INK pathway plays a critical role in acetaminophen-induced liver injury.
  • ASKl has also been reported to be involved in liver injury induced by troglitazone, a first- generation thiazolidinedione insulin sensitizer that has been linked to an unacceptable risk of liver injury in patients.
  • compounds described herein are used in the treatement of ageing.
  • ROS is thought to be one of the major causes of ageing.
  • long- lived mouse models such as Snell dwarf mice, Ames dwarf mice, and Klotho overexpressing mice, are known to be resistant to oxidative stress.
  • Mouse embryonic fibroblasts (MEFs) derived from Ames dwarf mice possess a larger amount of the Trx -bound form of ASKl and have less p38 activity than those derived from WT mice, suggesting that activity of the ASKl-p38 pathway is attenuated in Ames dwarf mice.
  • ROS-induced ASKl activity contributes to regulation of ageing-related cellular functions.
  • Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are ASKl inhibitors.
  • n 0, 1, 2, or 3;
  • Ci-C 6 alkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-C 6 deuteroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, or substituted or unsubstituted -Ci-C 4 alkylene-N(R 5 ) 2 ;
  • L 1 is linker that is -X 2 -, L 2 , -L 2 -X 2 -, -X 2 - L 3 -, or -L 2 -X 2 - L 3 -;
  • R 6 is H, Ci-C 6 alkyl, Ci-Cefluoroalkyl, or Ci-C 6 deuteroalkyl;
  • L 2 is substituted or unsubstituted Ci-C 4 alkylene, substituted or unsubstituted C 2 -
  • L 3 is Ci-C 4 alkylene
  • X 1 is CR 2 or N
  • X 2 is CR 2 or N
  • R 3 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-
  • ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl
  • each R 4 is independently selected from Ci-C 6 alkyl, Ci-Cefluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -Ci 0 cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl and substituted or unsubstituted heteroaryl;
  • each R 5 is independently selected from H, Ci-C 6 alkyl, Ci-Cefluoroalkyl, Ci-
  • substituents are selected from among a subset of the listed alternatives.
  • m is 0, 1, 2, or 3.
  • m is 0, 1, or 2.
  • m is 0 or 1.
  • p is 0, 1, 2, or 3. In other embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.
  • n is 0, 1, 2, or 3. In other embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.
  • ring A is phenyl, a 6-membered heteroaryl containing 1-3 N- atoms, a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5- membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
  • ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
  • X 6 is N or CR a .
  • ring A is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • each R a is independently selected from the group consisting of H, D, F, CI, Br, -CN, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , -OCD 3 , cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • each R a is independently selected from the group consisting of H, D, F, CI, Br, -CN, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , and -OCD 3 .
  • R 1 is H, D, F, CI, Br, -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , - OCH 2 CF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH2CF 3 , -CD 3 , - OCD 3 , -CH 2 NH 2 , CD 2 NH 2 , or CF 2 NH 2 .
  • R 1 is H or CF 2 NH 2 .
  • R 1 is -CH 2 NH 2 .
  • each R 2 is independently H, D, halogen, -CN, -OR 5 , -N(R 5 ) 2 , C C 6 alkyl, Ci-C 6 fluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
  • each R 2 is independently H, D, F, CI, -CN, -OH, -OCH 3 , - OCH 2 CH 3 , -OCF 3 , - H 2 , - HCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , - OCD 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each R 2 is independently H, D, F, CI, -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , or -OCD 3 .
  • each R 2 is independently H, D, F, CI, -CH 3 , -CF 3 , or -CD 3 .
  • each R 2 is independently H, F, or -CH 3 .
  • R 3 is H or Ci-C 6 alkyl. In some embodiments, R 3 is H or-CH 3 . In some embodiments, R 3 is H.
  • each R 4 is independently selected from Ci-C 6 alkyl, Ci- Cefluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 - C 6 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl and substituted or unsubstituted monocyclic heteroaryl.
  • each R 4 is independently selected from Ci- C 6 alkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl and substituted or unsubstituted monocyclic heteroaryl.
  • each R 5 is independently selected from H, Ci-C 6 alkyl, Ci- Cefiuoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 - C 6 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl and substituted or unsubstituted monocyclic heteroaryl; or two R 5 on the same N atom are taken together with the N atom to which they are attached to a substituted or unsubstituted N-containing monocyclic heterocycle.
  • each R 5 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl and substituted or unsubstituted monocyclic heteroaryl; or two R 5 on the same N atom are taken together with the N atom to which they are attached to a substituted or unsubstituted N- containing monocyclic heterocycle.
  • each R is independently H, D, halogen, -CN, -OR 5 , -SR 5 , d- C 6 alkyl, Ci-Cefluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
  • each R is independently H, D, F, CI, Br, -CN, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , or -OCD 3 .
  • each R is independently H, D, F, CI, -CN, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , or -OCD 3 .
  • each R is independently H, D, F, -OH, -OCH 3 , or -CH 3 .
  • each R is H. [0091]
  • each R c is independently H, D, halogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 fluoroalkyl, substituted or
  • Ci-C 6 deuteroalkyl substituted or unsubstituted Ci-C 6 heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl.
  • each R c is independently H, D, F, CI, -CH 3 , -CH 2 CH 3 , - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(CD 3 ) 2 , -CH(CF 3 ) 2 , -CH(CH 2 F) 2 , -CH 2 CH 2 CH 2 CH 3 , - CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 OH, - CH(CH 2 OH) 2 , -CH(CH 3 )(CH 2 OH), -CH(CH 3 )(CH 2 F),-CH(CHF) 2 , -CH(CH 2 CF 3 ) 2 , -CH 2 OCH 3 , - CH 2 OCH 2 CH
  • each R c is independently H, D, F, CI, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(CD 3 ) 2 , - CH(CF 3 ) 2 , -CH(CH 2 F) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 OH, -CH(CH 2 OH) 2 , -CH(CH 3 )(CH 2 OH), -CH(CH 3 )(CH 2 F),-CH(CH 2 F) 2 , -CH(CH 2 CF 3 ) 2 , cyclopropyl, fluorocyclopropyl, deuterocyclopropyl, or hydroxy cyclopropyl.
  • cyclopropyl fluorocyclopropyl, deuterocyclo
  • each R c is independently H, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(CD 3 ) 2 , -CH(CF 3 ) 2 , - CH(CH 2 F) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 OH, - CH(CH 2 OH) 2 , -CH(CH 3 )(CH 2 OH), -CH(CH 3 )(CH 2 F), -CH(CHF 2 ) 2 , -CH(CH 2 CF 3 ) 2 , cyclopropyl, fluorocyclopropyl, deuterocyclopropyl, or hydroxy cyclopropyl.
  • each R c is independently -CH(CH 3 ) 2 , -CH(CD 3 ) 2 , -CH(CF 3 ) 2 , -CH(CH 2 F) 2 , -CH(CH 2 CH 3 ) 2 , - CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 OH) 2 , -CH(CH 3 )(CH 2 OH), -CH(CH 3 )(CH 2 F), or cyclopropyl.
  • each R c is independently -CH(CH 3 ) 2 , or cyclopropyl.
  • L 1 is -X 2 -, L 2 , -L 2 -X 2 -, or -X 2 - L 3 -.
  • X 2 is -0-.
  • L 1 is -0-.
  • ring B is a 6-membered heteroaryl or phenyl.
  • ring B is a pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. [00100] In some embodiments, the groups
  • x 3 i s N or CR In some embodiments, is x 3 i s N or CR . In some embodiments,X 3 is N. In some embodiments,X 3 is CR
  • the compound of Formula (I) has the following structure of Formula (II), or a pharmaceutically acceptable salt, or solvate thereof:
  • X 3 is N or CR .
  • the compound of Formula (II) has one of the following structures, or a pharmaceutically acceptable salt, or solvate thereof:
  • X 4 is N or CR a : X 5 is N or CR a : X 6 is N or CR a .
  • ring B is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazan l.
  • ring C is a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5-membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
  • ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazan l.
  • X 7 is N. In some embodiments,X 7 is CR C .
  • the compound of Formula (I) has the following structure of Formula (III), or a pharmaceuticall acceptable salt, or solvate thereof:
  • X 2 is CR 2 or N;
  • X 3 is N or CR ;
  • X 7 is N or CR C .
  • a compound that inhibits apoptosis signal-regulating kinase (ASKl) activity and lysyl oxidase like-2 (LOXL2) activity is an aminoalkyl compound. In some embodiments, the compound is an aminomethyl compound. In some embodiments, the compound is an aminoalkylaryl or aminoalkylheteroaryl compound. In some embodiments, the compound is an aminomethylphenyl or
  • the compound has the structure of Formula (IV), or a pharmaceutically acceptable salt, or solvate thereof
  • ring A is a phenyl, 6-membered heteroaryl, or a 5-membered heteroaryl
  • n 0, 1, 2, or 3;
  • L 4 is Ci-C 4 alkylene, Ci-C 4 fluoroalkylene, or Ci-C 4 deuteroalkylene;
  • L 1 is linker that is -X 2 -, L 2 , -L 2 -X 2 -, -X 2 - L 3 -, or -L 2 -X 2 - L 3 -;
  • R 6 is H, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, or Ci-C 6 deuteroalkyl;
  • L 2 is substituted or unsubstituted Ci-C 4 alkylene, substituted or unsubstituted C 2 - C 4 alkenylene or substituted or unsubstituted C 2 -C 4 alkynylene;
  • L 3 is Ci-C 4 alkylene
  • X 2 is CR 2 or N
  • R 3 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-
  • Cefluoroalkyl or substituted or unsubstituted Ci-C 6 deuteroalkyl
  • ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl
  • ring C is a 5-membered heteroaryl
  • each R 4 is independently selected from Ci-C 6 alkyl, Ci-Cefluoroalkyl, Ci-C 6 deuteroalkyl, Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -Ci 0 cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl and substituted or unsubstituted heteroaryl;
  • each R 5 is independently selected from H, Ci-C 6 alkyl, Ci-Cefluoroalkyl, Ci-
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, or CD 2 -. In some embodiments, L 4 is -CH 2 -, -CF 2 -, or CD 2 -. In some embodiments, L 4 is -CH 2 -.
  • ring A is phenyl, a 6-membered heteroaryl containing 1-3 N- atoms, a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5- membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
  • ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, ring A is phenyl, pyridinyl, or pyrimidinyl. In some embodiments, ring A is phenyl, or pyridinyl. In some embodiments, ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments, ring A is pyridinyl, or pyrimidinyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyridazinyl. In some embodiments, ring A is phenyl.
  • X 6 is N or CR a .
  • X 4 is N or CR a ; X 5 is CR a ; X 6 is CR a .
  • X 4 is N; X 5 is CR a ; X 6 is CR a .
  • X 4 is N; X 5 is N; X 6 is CR a .
  • X 4 is N; X 5 is N; X 6 is CR a .
  • X 4 is N; X 5 is CR a ; X 6 is N.
  • X 4 is CR a ; X 5 is N; X 6 is N.
  • ring A is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • the compound of Formula (IV) has one of the following structures, or a pharmaceutically acceptable salt, or solvate thereof:
  • X 4 is N or CR a ;
  • X 5 is N or CR a ;
  • X 6 is N or CR a .
  • R c , X 2 , X 1 , and L 1 are as described herein.
  • R c , X 2 , X 1 , and L 1 are as described in Table 1 or Table 2.
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, or CD 2 -.
  • L 4 is -CH 2 -, -CF 2 -, or CD 2 -.
  • L 4 is -CH 2 -.
  • each R a is independently selected from the group consisting of H, D, F, CI, Br, -CN, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , -OCD 3 , cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • each R a is independently selected from the group consisting of H and -CF 3 .
  • R a is H or -CF 3 .
  • the compound of Formula (IV) has the following structure, or a pharmaceutically acceptable salt, or solvate thereof:
  • R c , X 2 , X 1 , and L 1 are as described herein.
  • R c , X 2 , X 1 , and L 1 are as described in Table 1 or Table 2.
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, or CD 2 -.
  • L 4 is -CH 2 -, -CF 2 -, or CD 2 -.
  • L 4 is -CH 2 -.
  • the compound of Formula (IV) has the following structure, or a pharmaceutically accepta le salt, or solvate thereof:
  • R c , X 2 , X 1 , and L 1 are as described herein.
  • R c , X 2 , X 1 , and L 1 are as described in Table 1 or Table 2.
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, or CD 2 -.
  • L 4 is -CH 2 -, -CF 2 -, or CD 2 -.
  • L 4 is -CH 2 -.
  • the compound of Formula (I) has the following structure, or a pharmaceutically acceptable salt, or solvate thereof:
  • R c , X 2 , X 1 , and L 1 are as described herein.
  • ( Ra , R c , X 2 , X 1 , and L 1 are as described in Table 1 or Table 2.
  • the compound of Formula (I) has the following structure, or a pharmaceutically acceptable salt, or solvate thereof:
  • R c , X 2 , X 1 , and L 1 are as described herein.
  • R c , X 2 , X 1 , and L 1 are as described in Table 1 or Table 2.
  • a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.
  • provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 2.
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use.
  • salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt- forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid.
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid;
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt. In some embodiments, a compound described herein is prepared as a hydrochloride salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base.
  • the compound described herein is acidic and is reacted with a base.
  • an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine,
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • the compounds provided herein are prepared as a sodium salt.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • N-oxides if appropriate
  • crystalline forms also known as polymorphs
  • pharmaceutically acceptable salts of compounds described herein as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not.
  • the prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • prodrug is a compound described herein, which is administered as an ester (the "prodrug") but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxy alkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al, Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. [00160] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a "metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • a transition metal catalyst such as Cu, Cul, or CuBr[PPh 3 ] 3 and in the presence of a base such as K 3 P0 4 or Cs 2 C0 3
  • a ligand such as 2-pyridinecarboxylic acid, 1 -methyl - lH-imidazole, N
  • compounds 1-6 and 1-7 may be prepared from 1-1 as follows. Introduction of a suitable protecting group (PG) for ZH resistant to alkali cleavage, followed by ester hydrolysis will afford 1-8. Treatment of 1-8 with 1-1 or 1-2 (prepared as described in Schemes 8 through 11) under standard amide coupling conditions, followed by deprotection of Z will give 1-10 or 1-11, respectively. Alternatively, treatment of carboxylic acid 1-8 with, for example, SOCl 2 or oxalyl chloride and catalytic DMF, in a suitable solvent such as DCM or THF will afford acid chloride 1-9.
  • (4H-[l,2,4]-triazol-3-yl)arylamide derivatives 2-6 or (1H- imidazol-5-yl)arylamide derivatives 2-7 are synthesized as shown in Scheme 2.
  • treatment of a hydroxyaryl derivative 2-1 with phenyl derivative 2-2 (Y halide) in the presence of a palladium catalyst such as Pd(OAc) 2 or Pd 2 (dba) 3 , in the presence of a base such as K 3 P0 4 or Cs 2 C0 3 , and in the presence of a ligand such as BINAP, or biphenyl-2-yl-di-tert-butylphospane, or XantPhos, heating in a suitable solvent such as toluene, or 1,4-dioxane and/or tert-butanol, can afford 2-3.
  • a palladium catalyst such as Pd(OAc) 2 or Pd 2 (dba) 3
  • a base such as K 3 P0 4 or Cs 2 C0 3
  • a ligand such as BINAP, or biphenyl-2-yl-di-tert-butylphospane, or XantP
  • (4H-[l,2,4]-triazol-3-yl)arylamide derivatives 4-7 or (1H- imidazol-5-yl)arylamide derivatives 4-8 are synthesized as shown in Scheme 4.
  • amide- derivative 4-4 treatment of carboxylic acid derivative 4-1 with a substituted aniline or heteroarylamine 4-3 using standard amide coupling conditions will afford amide- derivative 4-4.
  • treatment of carboxylic acid 4-1 with, for example, SOCl 2 or oxalyl chloride and catalytic DMF, in a suitable solvent such as DCM or THF will afford acid chloride 4-2.
  • Subsequent treatment of acid chloride 4-2 with 4-3 in the presence of a suitable base such as TEA, Hunig's base, NaHC0 3 , or K 2 C0 3 , and in a suitable solvent such as DCM or THF, with or without an activating agent such as DMAP, with or without heating, will afford 4-4.
  • Acid derivative 4-5 may be converted to either 4-7 or 4-8 via reaction with I-l or 1-2 (prepared as described in Schemes 8 through 11), respectively, using methods described in Scheme 1.
  • PG carboxylic protecting group
  • R Me, Et
  • treatment of amino-derivative 5-1 with a heteroarylcarboxylic acid or benzoic acid 5-2 using standard amide coupling conditions will afford amide-derivative 5-4.
  • treatment of amino-derivative 5-1 with heteroaryl acid chloride or benzoyl chloride 5-3 in the presence of a suitable base such as TEA, Hunig's base, NaHC0 3 , or K 2 C0 3 , and in a suitable solvent such as DCM or THF, with or without an activating agent such as DMAP, with or without heating will afford 5-4.
  • a suitable base such as TEA, Hunig's base, NaHC0 3 , or K 2 C0 3
  • a suitable solvent such as DCM or THF
  • an activating agent such as DMAP
  • Acid derivative 5-5 may be converted to either 5-7 or 5-8 via reaction with I-l or 1-2 (prepared as described in Schemes 8 through 11), respectively, using methods described in Scheme 1.
  • compounds 5-7 and 5-8 may be prepared from 5-1 as follows.
  • PG amine protecting group
  • R Me, Et
  • amino-derivative 6-1 (Z R) with methyl halide derivative 6-2 in the presence of a suitable base such as TEA, Hunig's base, NaH, K 2 C0 3 , NaOH, NaHC0 3 , and in a suitable solvent such as DMF, DMA, DMSO, MeCN, 1,4-dioxane, or THF, with or without an activating agent such as TBAI, AgN0 3 , or a crown ether, with or without heating, will afford 6-3. Subsequent treatment of 6-3 with LiOH in aqueous THF will give carboxylic acid derivative 6-4.
  • a suitable base such as TEA, Hunig's base, NaH, K 2 C0 3 , NaOH, NaHC0 3
  • a suitable solvent such as DMF, DMA, DMSO, MeCN, 1,4-dioxane, or THF
  • an activating agent such as TBAI, AgN0 3 , or a crown ether
  • Acid derivative 6-4 may be converted to either 6-6 or 6-7 via reaction with I-l or 1-2 (prepared as described in Schemes 8 through 11), respectively, using methods described in Scheme 1.
  • 6-8 Treatment of 6-8 with aminopyridine derivatives I-l or 1-2 (prepared as described in Schemes 8 through 11) under standard amide coupling conditions, followed by deprotection of Z will give 6-10 or 6-11, respectively.
  • aryl halide derivative 7-1 with acetylene derivative 7-2 in the presence of a palladium catalyst such as for example Pd[PPh 3 ] 4 or Pd[PPh 3 ] 2 Cl 2 , and in the presence of Cul, and in the presence of a base such as TEA or hunig's base, and in a suitable solvent such as toluene, DMF, DMA, MeCN, or THF, will give 7-3.
  • a suitable solvent such as toluene, DMF, DMA, MeCN, or THF
  • compounds 7-6 and 7-7 may be prepared from 7-1 as follows. Treatment of 7-1 with LiOH in aqueous THF, will afford carboxylic acid derivative 7-8. Treatment of 7-8 with I-l or 1-2 (prepared as described in Schemes 8 through 11) under standard amide coupling conditions, will give 7-10 or 7-11, respectively. Alternatively, treatment of carboxylic acid 7-8 with, for example, oxalyl chloride and catalytic DMF, in a suitable solvent such as DCM or THF will afford acid chloride 7-9.
  • (4H-[l,2,4]-triazol-3-yl)arylamine derivatives 1-1 are synthesized as shown in Scheme 8.
  • aryl-ester derivatives 8-1 can be converted to the corresponding hydrazides 8-2, via treatment of 8-1 with hydrazine in a suitable solvent such as MeOH or EtOH with heating. Hydrazide derivatives 8-2 upon heating with DMF-DMA can afford 8-3. Reaction of 8-3 with a primary amine (R C H 2 ) in the presence of HO Ac and in a suitable solvent such as MeCN with heating, will give 1-1.
  • the amino group of 9-1 may be protected with appropriate protecting groups (PG) to give 9-2.
  • PG protecting groups
  • Heating of 9-3 with a primary amine (R C H 2 ) and a formamide of formula R c HCHO, in the presence of a suitable acid such as TFA, and in a suitable solvent such as toluene, will give 9-4. Subsequent amine deprotection of 9-4 will afford 1-1.
  • (lH-imidazol-5-yl)arylamine derivatives 1-2 are synthesized as shown in Scheme 11.
  • arylamine derivative 11-1 treatment of arylamine derivative 11-1 with di-tert-butyl dicarbonate, in the presence of a suitable base such as TEA or Hunig's base, and in the presence of an activating agent such as DMAP, and in a suitable solvent such as THF, DCM, or tert- butanol, with or without heating, will afford 11-2.
  • a suitable base such as TEA or Hunig's base
  • an activating agent such as DMAP
  • a suitable solvent such as THF, DCM, or tert- butanol
  • Ci-C x includes C 1 -C 2 , C 1 -C3 . . . Ci-C x .
  • a group designated as “C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, z ' so-propyl, «-butyl, /so-butyl, sec-butyl, and t-butyl.
  • an "alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the "alkyl” group has 1 to 10 carbon atoms, i.e. a Ci- C 10 alkyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., " 1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • an alkyl is a Ci-C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • alkyl ene group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkelene is a Ci-C 6 alkylene. In other words,
  • an alkylene is a Cioalkyl ene.
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkynyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • alkoxy refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl ("aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
  • pyridine e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon.
  • at least one of the two rings of a bicyclic carbocycle is aromatic.
  • both rings of a bicyclic carbocycle are aromatic.
  • bicyclic carbocycles are fused, bridged or spirocyclic.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a C 6 -Cioaryl.
  • an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[l . l . l]pentyl.
  • a cycloalkyl is a C 3 - C 6 cycloalkyl.
  • halo or, alternatively, "halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoralkyl is a Ci-Cefluoroalkyl.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-l-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • bicyclic heterocycles are fused, bridged or spirocyclic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a Ci-C 9 heteroaryl.
  • monocyclic heteroaryl is a Ci-C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a Ce-Cgheteroaryl.
  • heterocycloalkyl or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 - Cioheterocycloalkyl.
  • a heterocycloalkyl is a C 4 -Ci 0 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bicyclic heterocycloalkyls are fused, bridged or spirocyclic.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule.
  • optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an antagonist.
  • a modulator is a degrader.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • the term "pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the term "subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the compounds described herein are formulated into
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes
  • injection or infusion including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
  • topical application such as creams or ointments, injection, catheter, or implant.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain
  • aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions may be administered topically, that is by non-systemic administration.
  • non-systemic administration includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10%) w/w, for instance from 1%> to 2% by weight of the formulation.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of ASK1 activity.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • therapeutic agents in certain embodiments, are administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
  • Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 and the ED 50 .
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the pharmaceutical composition further comprises one or more anti-cancer agents.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • factors e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject.
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is administered in combination with chemotherapy, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof.
  • Chemotherapy includes the use of anti-cancer agents.
  • the compound described herein, or a pharmaceutically acceptable salt thereof is administered or formulated in combination with one or more anti -cancer agents.
  • Step 2 (E)-A ⁇ -(6-((E)-2-((Dimethylamino)methylene)hydrazinecarbonyl)pyridin-2-yl)-N ⁇ V- dimethylformimidamide (A-3)
  • a stirred mixture of A-2 (23 g, 151 mmol) in DMF-DMA (200 mL) was heated at 110 °C for 24 h.
  • the mixture was cooled to rt then concentrated under reduced pressure.
  • the solid residue was re-suspended in EtOAc (150 mL) and stirred at 50 °C for 20 min.
  • the mixture was cooled to rt and Et 2 0 (100 mL) was added.
  • the solids were collected via filtration, washed with Et 2 0, and dried to afford compound A-3 (36.5 g, 92%) as a light yellow solid.
  • Step 2 2-Fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-5-nitrobenzamide (B- 3)
  • Step 3 5-Amino-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)benzamide (Int-B)
  • Step 3 Benzyl (6-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)carbamate (C-4)
  • Step 4 6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-amine (Int-C)
  • Step 1 Benzyl (3-(l,3,4-oxadiazol-2-yl)phenyl)carbamate (D-2)
  • Step 2 Benzyl (3-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)phenyl)carbamate (D-3)
  • Int-E was prepared using the procedure described for Int-A, using l,3-difluoropropan-2- hydrochloride in Step 3.
  • Step 1 (R)-2-(3-(6-Aminopyridin-2-yl)-4H-l,2,4-triazol-4-yl)propan-l-ol (F-2)
  • Step 2 (R)-6-(4-(l-((teri-Butyldimethylsilyl)oxy)propan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin- 2-amine (F-3)
  • Step 3 (R)-N-(6-(4-(l-((teri-butyldimethylsilyl)oxy)propan-2-yl)-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-2-fluoro-5-nitrobenzamide (F-4)
  • Step 4 (R)-5-Amino-N-(6-(4-(l-((teri-butyldimethylsilyl)oxy)propan-2-yl)-4H-l,2,4-triazol- 3-yl)pyridin-2-yl)-2-fluorobenzamide (Int-F)
  • Step 1 N-(6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3-(pyridin-3- ylmethoxy)benzamide (1)
  • Step 2 N-(6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3-(pyridin-3- ylmethoxy)benzamide hydrochloride (Compound 1-181)
  • Step 3 2-Fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-5-(pyridin-2-yloxy) benzamide hydrochloride (Compound 1-210)
  • Step 4 2-Fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-5-(pyridin-3- yloxy)benzamide hydrochloride (Compound 1-211)
  • a stirred mixture A stirred mixture of 2,6-dibromopyridine (1.9 g, 8.08 mmol), cyclopropylboronic acid (1.37 g, 16.17 mmol), Cs 2 C0 3 (7.8 g, 24.2 mmol), Pd(PPh 3 ) 4 (464 mg, 0.401 mmol), and 1,4-dioxane (32 mL) under an inert atmosphere, was heated at 100 °C for 1 h. The mixture was cooled to rt and filtered through a pad of celite, and the celite further washed with EtOAc (2 ⁇ 75 mL).
  • Step 3 5-((6-Cyclopropylpyridin-2-yl)oxy)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)benzamide trifluoroacetate (Compound 1-213)
  • Step 2 2-Fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-5-(pyrimidin-4- yloxy)benzamide (2) [00290] The title compound (90 mg, 13%) was prepared from compound 1 using the procedure described for Example 5, Step 2.

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Abstract

La présente invention concerne des inhibiteurs de ASK1, des procédés de production de ces composés, des compositions pharmaceutiques et des médicaments comprenant lesdits composés, ainsi que des procédés d'utilisation de ces composés pour traiter des états pathologiques, des maladies ou des troubles associés à l'activité de ASK1.
PCT/US2018/024130 2017-03-27 2018-03-23 Composés inhibiteurs de kinase 1 (ask 1) de régulation du signal de l'apoptose WO2018183122A1 (fr)

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WO2019213244A1 (fr) 2018-05-02 2019-11-07 Enanta Pharmaceuticals, Inc. Inhibiteurs de la kinase 1 régulant le signal d'apoptose contenant des tétrazoles et leurs méthodes d'utilisation
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US10968199B2 (en) 2018-08-22 2021-04-06 Enanta Pharmaceuticals, Inc. Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
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